U.S. patent application number 11/454859 was filed with the patent office on 2007-01-18 for novel phenylboronic acid compounds and intermediates and processes for the preparation thereof.
This patent application is currently assigned to GALDERMA RESEARCH & DEVELOPMENT. Invention is credited to Jean-Claude Pascal, Eric Terranova.
Application Number | 20070015931 11/454859 |
Document ID | / |
Family ID | 34630315 |
Filed Date | 2007-01-18 |
United States Patent
Application |
20070015931 |
Kind Code |
A1 |
Terranova; Eric ; et
al. |
January 18, 2007 |
Novel phenylboronic acid compounds and intermediates and processes
for the preparation thereof
Abstract
Vitamin D derivatives, notably non-steroidal vitamin D
derivatives, are prepared from novel disubstituted phenylboronic
acid compounds having the formula (I): ##STR1## and also from the
novel intermediates having the formulae (1), (2), (3) and (10):
##STR2##
Inventors: |
Terranova; Eric; (Magagnosc,
FR) ; Pascal; Jean-Claude; (Nice, FR) |
Correspondence
Address: |
BUCHANAN, INGERSOLL & ROONEY PC
POST OFFICE BOX 1404
ALEXANDRIA
VA
22313-1404
US
|
Assignee: |
GALDERMA RESEARCH &
DEVELOPMENT
BOIT
FR
|
Family ID: |
34630315 |
Appl. No.: |
11/454859 |
Filed: |
June 19, 2006 |
Current U.S.
Class: |
558/287 ;
562/7 |
Current CPC
Class: |
C07C 69/76 20130101;
C07F 5/025 20130101; C07C 33/20 20130101; C07C 43/23 20130101; C07C
39/15 20130101; C07C 401/00 20130101 |
Class at
Publication: |
558/287 ;
562/007 |
International
Class: |
C07F 5/02 20060101
C07F005/02 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 18, 2003 |
FR |
03/14946 |
Dec 10, 2004 |
WO |
PCT/FR04/03192 |
Claims
1. A disubstituted phenylboronic acid compound having the following
structural formula (I): ##STR36## in which: R1 is a hydrogen atom
or an alkyl radical having from 1 to 4 carbon atoms, R2 and R3,
which may be identical or different, are each an alkyl radical
having from 1 to 4 carbon atoms, and R4 is the --B(OH).sub.2
radical or the radical of formula: ##STR37##
2. The disubstituted phenylboronic acid compound as defined by
claim 1, wherein formula (I), each alkyl radical having from 1 to 4
carbon atoms is a saturated or unsaturated, linear or cyclic,
optionally branched such radical and can be interrupted by a
heteroatom.
3. The disubstituted phenylboronic acid compound as defined by
claim 2, wherein formula (I), each alkyl radial is selected from
the group consisting of methyl, ethyl, propyl, isopropyl,
cyclopropyl, butyl, isobutyl and tert-butyl radicals.
4. The compound having the following structural formula (1):
##STR38##
5. A compound having the following structural formula (2):
##STR39## in which: R.sub.5 is an alkyl radical having from 1 to 4
carbon atoms.
6. A compound having the following structural formula (3):
##STR40## in which R1 is a hydrogen atom or an alkyl radical having
from 1 to 4 carbon atoms, and R2 and R3, which may be identical or
different, are each an alkyl radical having from 1 to 4 carbon
atoms.
7. A compound having the following structural formula (10):
##STR41## in which: R1 is a hydrogen atom or an alkyl radical
having from 1 to 4 carbon atoms, R2 and R3, which may be identical
or different, are each an alkyl radical having from 1 to 4 carbon
atoms, and R'.sub.1 is an alkyl radical having from 1 to 4 carbon
atoms.
8. A process for the preparation of a disubstituted phenylboronic
acid compound (I) as defined by claim 1 wherein formula (I) R4 is
the B(OH).sub.2 radical, comprising: a) bromination of methyl
4-bromo-3-methylbenzoate into the compound (1): ##STR42## b)
substituting the bromine atom introduced in step a) by an alkyl
radical R5 having from 1 to 4 carbon atoms to obtain a compound
(2): ##STR43## c) converting the ester function of the intermediate
(2) or of methyl 4-bromo-3-methylbenzoate into a tertiary alcohol
function by reaction with an organomagnesium compound of formula
R2-MgX wherein X is a halogen and R2 is a methyl, ethyl, propyl or
butyl radical, to obtain a compound (3): ##STR44## d) converting
the intermediate (3) into said disubstituted phenylboronic acid
compound (I) in the presence of a base and a trialkyl borate, with
the proviso that the steps a) and b) are omitted in the event that
R1 is a hydrogen atom.
9. A process for the preparation of a disubstituted phenylboronic
acid compound as defined by claim 1 wherein formula (I) R4 is the
##STR45## a) bromination of methyl 4-bromo-3-methylbenzoate into
the compound (1): ##STR46## b) substituting the bromine atom
introduced in step a) by an alkyl radical R5 having from 1 to 4
carbon atoms to obtain a compound (2): ##STR47## c) converting the
ester function of the intermediate (2) or of methyl
4-bromo-3-methylbenzoate into a tertiary alcohol function by
reaction with an organomagnesium compound of formula R2-MgX wherein
X is a halogen and R2 is a methyl, ethyl, propyl or butyl radical,
to obtain a compound (3): ##STR48## d) converting the intermediate
(3) into an aryl boronate in the presence of a base and a boron
tetraalkyl and then into said disubstituted phenylboronic acid
compound (I), with the proviso that the steps a) and b) are omitted
in the event that R1 is a hydrogen atom.
10. The process as defined by claims 8 or 9, wherein step a) is
carried out in the presence of at least one brominating agent
selected from the group consisting of bromine, N-bromosuccinimide,
sodium bromate and 1,3-dibromo-5,5-dimethylhydantoin and in a
chlorinated or ether solvent.
11. The process as defined by claim 10, wherein step a) is carried
out in the presence of N-bromosuccinimide in dichloromethane.
12. The process as defined by claims 8 or 9, wherein step a) is
carried out in the presence of a free-radical initiator.
13. The process as defined by claims 8 or 9, wherein step b) is
carried out in the presence of an organometallic reagent R'1-M in
which M is magnesium, copper or zinc.
14. The process as defined by claim 13, wherein step b) is carried
out in the presence of copper iodide and an organomagnesium
compound R'1-MgX in which X is a bromine, chlorine or iodine
atom.
15. The process as defined by claims 8 or 9, wherein step b) is
carried out in an ethereal solvent.
16. The process as defined by claims 8 or 9, wherein step b) is
carried out at a temperature of from 40.degree. C. to -20.degree.
C.
17. The process as defined by claims 8 or 9, wherein step c) is
carried out in an ethereal solvent at a temperature of from
-10.degree. C. to +10.degree. C.
18. The process as defined by claim 8, wherein step d) is carried
out in the presence of an ethereal solvent, a strong base and a
trialkyl borate.
19. The process as defined by claim 18, wherein step d) is carried
out in the presence of tetrahydrofuran, butyllithium and
triisopropyl borate, at a temperature of from -78.degree. C. to
40.degree. C.
20. The process as defined by claim 9, wherein step d) is carried
out in the presence of a DMF, tetrahydrofuran, DMSO or dioxane
solvent, a
dichloro[1,1'-ferrocenylbis(diphenylphosphane)]palladium(II)
dichloromethane or Pd(dppf)Cl.sub.2 catalyst, a potassium acetate
or triethylamine base, and pinacolborane or pinacoldiborane.
21. A non-steroidal vitamin D analogue prepared from a
disubstituted phenylboronic acid compound as defined by claim
1.
22. The non-steroidal vitamin D analogue as defined by claim 21,
having the structural formula (IV): ##STR49## in which: R1 is a
hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms,
R2 and R3, which may be identical or different, are each an alkyl
radical having from 1 to 4 carbon atoms, and R'.sub.1 is an alkyl
radical having from 1 to 4 carbon atoms.
23. A process for the preparation of a non-steroidal vitamin D
analogue as defined by claim 22, comprising: a) Suzuki coupling a
compound having the formula (I): ##STR50## in which: R1 is a
hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms,
R2 and R3, which may be identical or different, are each an alkyl
radical having from 1 to 4 carbon atoms, and R4 is the
--B(OH).sub.2 radical or the radical of formula: ##STR51## and an
aryl bromide having the formula (II): ##STR52## in which: R'.sub.1
is an alkyl radical having from 1 to 4 carbon atoms, to obtain a
compound of formula (10): ##STR53## b) fusing the Suzuki reaction
compound (1) with the benzyl bromide (11) in the presence of a
base: ##STR54## c) liberating the alcohol functions of the compound
(11) to obtain the compound (IV).
Description
CROSS-REFERENCE TO PRIORITY/PCT APPLICATIONS
[0001] This application claims priority under 35 U.S.C. .sctn. 119
of FR 03/14946, filed Dec. 18, 2003, and is a continuation of
PCT/FR 2004/003192, filed Dec. 10, 2004 and designating the United
States (published in the French language on Jul. 7, 2005 as WO
2005/061520 A1; the title and abstract were also published in
English), each hereby expressly incorporated by reference and each
assigned to the assignee hereof.
SUMMARY OF THE INVENTION
[0002] The present invention relates to novel disubstituted
derivatives of phenylboronic acid, having the general formula (I):
##STR3## in which:
[0003] R1 is a hydrogen atom or an alkyl radical having from 1 to 4
carbon atoms,
[0004] R2 and R3, which may be identical or different, are each an
alkyl radical having from 1 to 4 carbon atoms,
[0005] R4 is the --B(OH).sub.2 radical or the radical of formula:
##STR4## to processes for the preparation thereof and to their use
as intermediates in the synthesis of non-steroidal vitamin D
derivatives.
[0006] Phenylboronic acid derivatives can be employed in
Suzuki-type coupling reactions and are important intermediates in
the synthesis of non-steroidal vitamin D3 analogues. Such reactions
have been described by the assignee hereof in WO 03/050067.
[0007] In WO 03/050067 the non-steroidal vitamin D derivatives of
general formula (IVa) (see FIG. 1) are obtained from intermediate
triflates of general formula (5) and boronic acid intermediates of
general formula (6).
[0008] The preparation of the intermediate triflates of general
formula (5) involves 3 synthesis steps and that of the boronic acid
intermediates of general formula (6) involves 6 synthesis
steps.
[0009] In the present invention the synthesis of the phenylboronic
acids of general formula (Ia) takes place in 4 steps and involves
the use of bromo derivatives of general formula (II) to obtain the
non-steroidal vitamin D derivatives of general formula (IVa)
according to FIG. 2. The bromo derivatives of general formula (II)
are prepared in 3 steps.
[0010] The use of the phenylboronic acids of general formula (I) of
the present invention therefore exhibits as its first advantage
access to the biphenyl intermediates of general formula (III) in 7
steps in total (see FIG. 2), whereas the synthesis described
previously, in WO 03/050067, involves 9 steps for access to the
biphenyl intermediates of general formula (7) (FIG. 1).
[0011] The use of the phenylboronic acids of general formula (I)
involves the utilization of bromo derivatives of general formula
(II), which exhibits as a second advantage the avoidance of the
protection and deprotection steps required in order to prepare the
boronic acid intermediates of general formula (6) that are used in
the preceding synthesis (FIG. 1). Moreover, the protection step was
carried out with methoxymethyl chloride, a highly carcinogenic
reactant which is prohibited on the industrial scale.
[0012] A third advantage provided by the use of the phenylboronic
acids of general formula (I) is that they allow access to the
biphenyl intermediates of general formula (III), in which the
tertiary alcohol function is already present, whereas by proceeding
via the biphenyl intermediates of general formula (7) as described
in WO 03/050067 (FIG. 1) it is still necessary to convert the
ketone function into a tertiary alcohol function.
[0013] A fourth advantage provided by the use of the phenylboronic
acids of general formula (I) is that they allow access to the
non-steroidal vitamin D derivatives of general formula (IVa) in
fewer steps than with the synthesis as described in WO 03/050067
and with a better yield.
[0014] In the present invention novel phenylboronic acid
derivatives have been synthesized via a novel process, which allows
the above problems to be remedied.
[0015] The present invention thus features novel disubstituted
derivatives of phenylboronic acid, having the general formula (I):
##STR5## in which:
[0016] R1 is a hydrogen atom or an alkyl radical having from 1 to 4
carbon atoms,
[0017] R2 and R3, which may be identical or different, are each an
alkyl radical having from of 1 to 4 carbon atoms, and
[0018] R4 is the --B(OH).sub.2 radical or the radical of formula:
##STR6##
BRIEF DESCRIPTION OF THE DRAWINGS
[0019] FIGS. 1-4 illustrate a variety of reaction schemes for the
ultimate preparation of the compounds of formula (I).
DETAILED DESCRIPTION OF BEST MODE AND SPECIFIC/PREFERRED
EMBODIMENTS OF THE INVENTION
[0020] According to the present invention an alkyl radical having 1
to 4 carbon atoms is a saturated or unsaturated, linear or cyclic,
optionally branched radical which contains 1 to 4 carbon atoms and
can be interrupted by a heteroatom, and preferably the alkyl
radicals having 1 to 4 carbon atoms are methyl, ethyl, propyl,
isopropyl, cyclopropyl, butyl, isobutyl or tert-butyl radicals.
[0021] The present invention also features the following novel
intermediate compounds: ##STR7##
[0022] Where, for compounds (2) and (3), R1 is a hydrogen atom or
an alkyl radical having from 1 to 4 carbon atoms, R2 and R3, which
may be identical or different, are each an alkyl radical having
from 1 to 4 carbon atoms and R.sub.5 is an alkyl radical having
from 1 to 4 carbon atoms.
[0023] The present invention likewise features employing the
compounds (1), (2) and (3) for preparing non-steroidal vitamin D
analogues and, in particular, as synthesis intermediates for
preparing compounds of formula (I) according to the invention.
[0024] This invention, therefore, also features a process for
synthesizing the subject novel phenylboronic acid derivatives of
formula (I).
[0025] The synthesis of these novel phenylboronic acid compounds of
general formula (I) in which R4 is the B(OH).sub.2 radical is
carried out in 4 steps starting from methyl
4-bromo-3-methylbenzoate (commercial product) according to the
scheme of FIG. 3.
[0026] Therefore, the process for preparing compounds of general
formula (I) in which R4 is the B(OH).sub.2 radical comprises the
following steps, steps a) and b) not being implemented in the
specific case in which R1 is a hydrogen atom:
[0027] a) bromination in the benzylic position in the presence of a
solvent, to give the compound (1): ##STR8##
[0028] b) substitution of the bromine introduced in step a) in the
benzylic position by an alkyl chain R.sub.5 containing 1 to 4
carbon atoms, to give the compound (2) as defined above:
##STR9##
[0029] c) conversion of the ester function of the intermediates of
general formula (2) or of methyl 4-bromo-3-methylbenzoate into a
tertiary alcohol function, using at least two equivalents of an
organomagnesium compound of formula R2-MgX
[0030] wherein X is a chlorine or bromine atom
[0031] and R2 is a methyl, ethyl, propyl or butyl radical, to give
the compound of general formula (3) as defined above: ##STR10##
[0032] d) conversion of the aromatic bromide of the intermediates
of general formula (3) into phenylboronic acid of formula (I) in
the presence of a solvent, a base and a trialkyl borate.
[0033] In greater detail, the steps of this process may be carried
out as follows:
[0034] a. The first step entails performing a bromination in the
benzylic position to give the intermediate (1). This halogenation
reaction is described in the literature. Various brominating agents
may be used, such as, for example, bromine (K. Smith et al., J.
Chem. Soc. Perkin. Trans., 1, 2000, 2745), N-bromosuccinimide (P.
Liu et al., Synthesis, 2001, 2078), sodium bromate (D. Kikuchi et
al., J. Org. Chem., 1998, 6023) or else
1,3-dibromo-5,5-dimethylhydantoin (H. Jendralla et al., Liebigs
Ann. Chem., 1995, 1253). This reaction is carried out most often in
chlorinated solvents or in ethers. The brominating agent used with
preference is N-bromosuccinimide at dichloromethane reflux.
Preferably, benzoyl peroxide is also used, in a catalytic amount,
as a free-radical reaction initiator. In order to activate the
free-radical reaction the reaction mixture is irradiated with a
1000 watt lamp.
[0035] This step provides the intermediate (1): ##STR11##
[0036] b. The second step entails substituting the bromine
introduced in step 1 in the benzylic position by an alkyl chain R'1
containing 1 to 4 carbon atoms. In order to promote this
substitution reaction the nucleophilic character of the alkyl group
R'1 is increased by using an organometallic reagent R'1-M in which
M is a metal atom such as magnesium, copper or else zinc. This
reaction is described in the literature (B. H. Lipshutz and S.
Sengupta, Organic Reactions, 1992, 41, 135). Preferably, copper in
the form of copper iodide is employed in the presence of an
organomagnesium compound R'1-MgX (X=Br, Cl, I) in order to generate
an organocuprate. This reaction may be carried out in ethereal
solvents. Preferably the ethereal solvent used is tetrahydrofuran.
The reaction is carried out at low temperature, preferably from
-40.degree. C. and 0.degree. C., more particularly from -40.degree.
C. and -20.degree. C.
[0037] This step provides the intermediates of general formula (2),
the radicals of which are defined above. ##STR12##
[0038] c. The third step entails converting the ester function of
the intermediates of general formula (2) or of methyl
4-bromo-3-methylbenzoate into a tertiary alcohol function, using at
least two equivalents of an organomagnesium compound of formula
R2-MgX, wherein X is a chlorine, bromine or iodine atom and R2 is
an alkyl radical having 1 to 4 carbon atoms. This reaction is
widely described in the literature. This reaction may be carried
out in ethereal solvents. Preferably, the ethereal solvent used is
tetrahydrofuran. The reaction is preferably carried out at a
temperature of from -20.degree. C. and +20.degree. C., more
particularly from -10.degree. C. and +10.degree. C.
[0039] This step provides the intermediates of general formula (3),
the radicals of which are defined above. ##STR13##
[0040] d. The fourth step entails converting the aromatic bromide
of the intermediates of general formula (3) into phenylboronic acid
of formula (I). This reaction, which is well documented in the
literature (N. Miyaura & A. Suzuki, Chem. Rev., 1995, 95,
2457), is carried out in tetrahydrofuran at temperatures of from
-78.degree. C. and -20.degree. C., preferably from -78.degree. C.
and -40.degree. C. From 2 and 4 equivalents of a strong base are
used such as butyllithium, preferably from 2.5 and 3.5 equivalents,
and a trialkyl borate is used, such as trimethyl borate or
triisopropyl borate. From 2 and 4 equivalents of the latter are
used, preferably from 2.5 and 3.5 equivalents.
[0041] According to another embodiment according to the invention,
the synthesis of these novel phenylboronic acid derivatives of
general formula (I) in which R4 is the radical of formula:
##STR14## is carried out in 4 steps starting from methyl
4-bromo-3-methylbenzoate (commercial product) according to the
scheme of FIG. 3.
[0042] The first three steps are similar to the process described
above.
[0043] Therefore, the process for preparing compounds of general
formula (I) in which R4 is the ##STR15## radical comprises the
following steps, steps a) and b) not being implemented in the
specific case in which R1 is a hydrogen atom:
[0044] a) bromination in the benzylic position in the presence of a
solvent, to give the compound (1): ##STR16##
[0045] b) substitution of the bromine introduced in step a) in the
benzylic position by an alkyl chain R.sub.5 containing 1 to 4
carbon atoms, to give the compound (2) as defined above:
##STR17##
[0046] c) conversion of the ester function of the intermediates of
general formula (2) or of methyl 4-bromo-3-methylbenzoate into a
tertiary alcohol function, using at least two equivalents of an
organomagnesium compound of formula R2-MgX
[0047] wherein X is a chlorine or bromine atom
[0048] and R2 is a methyl, ethyl, propyl, butyl or isobutyl radical
to give the compound of general formula (3) as defined above:
##STR18##
[0049] d) conversion of the aromatic bromide into aryl boronate in
the presence of a solvent, a catalyst, a base and pinacolborane or
pinacoldiborane, to give the compound of general formula (I).
[0050] In greater detail, the steps of this process may be carried
out as follows:
[0051] a. The first step entails performing a bromination in the
benzylic position to give the intermediate (1). This halogenation
reaction is described in the literature. Various brominating agents
may be used, such as, for example, bromine (K. Smith et al., J.
Chem. Soc. Perkin. Trans., I, 2000, 2745), N-bromosuccinimide (P.
Liu et al., Synthesis, 2001, 2078), sodium bromate (D. Kikuchi et
al., J. Org. Chem., 1998, 6023) or else
1,3-dibromo-5,5-dimethylhydantoin (H. Jendralla et al., Liebigs
Ann. Chem., 1995, 1253). This reaction is carried out most often in
chlorinated solvents or in ethers. The brominating agent used with
preference is N-bromosuccinimide at dichloromethane reflux.
Preferably, benzoyl peroxide is also used, in a catalytic amount,
as a free-radical reaction initiator. In order to activate the
free-radical reaction the reaction mixture is irradiated with a
1000 watt lamp.
[0052] This step provides the intermediate (1): ##STR19##
[0053] b. The second step entails substituting the bromine
introduced in step 1 in the benzylic position by an alkyl chain R'1
containing 1 to 4 carbon atoms. In order to promote this
substitution reaction the nucleophilic character of the alkyl group
R'1 is increased by using an organometallic reagent R'1-M in which
M is a metal atom such as magnesium, copper or else zinc. This
reaction is documented in the literature (B. H. Lipshutz and S.
Sengupta, Organic Reactions, 1992, 41, 135). Preferably, copper in
the form of copper iodide is employed in the presence of an
organomagnesium compound R'1-MgX (X=Br, Cl, I) in order to generate
an organocuprate. This reaction may be carried out in ethereal
solvents. Preferably the ethereal solvent used is tetrahydrofuran.
The reaction is carried out at low temperature, preferably from
-40.degree. C. and 0.degree. C., more particularly from 40.degree.
C. and -20.degree. C.
[0054] This step provides the intermediates of general formula (2),
the radicals of which are defined above. ##STR20##
[0055] c. The third step entails converting the ester function of
the intermediates of general formula (2) or of methyl
4-bromo-3-methylbenzoate into a tertiary alcohol function, using at
least two equivalents of an organomagnesium compound of formula
R2-MgX, wherein X is a chlorine, bromine or iodine atom and R2 is
an alkyl radical having 1 to 4 carbon atoms. This reaction is
widely described in the literature. This reaction may be carried
out in ethereal solvents. Preferably, the ethereal solvent used is
tetrahydrofuran. The reaction is preferably carried out at a
temperature of from -20.degree. C. and +20.degree. C., more
particularly from -10.degree. C. and +10.degree. C.
[0056] This step provides the intermediates of general formula (3),
the radicals of which are defined above. ##STR21##
[0057] d. In this fourth step, the aromatic bromide of the
intermediates of general formula (3) may be converted into aryl
boronate. This reaction, which is also well described in the
literature (a/ M. Murata et al., J. Org. Chem., 1997, 62, 6458; b/
T. Ishiyama et al., J. Org. Chem., 1995, 60, 7508), is carried out
in solvents such as DMF, tetrahydrofuran, DMSO or else dioxane. The
reaction temperatures used are generally close to the reflux
temperatures of the solvents. Generally, use is made of a palladium
catalyst, preferably
dichloro[1,1'-ferrocenylbis(diphenylphosphane)]palladium(II)
dichloromethane or Pd(dppf)Cl.sub.2, a base, preferably potassium
acetate or triethylamine, preferably from 2.5 and 3.5 equivalents,
and a boron tetraalkoxide, preferably pinacolborane or
pinacoldiborane. From 1 and 1.5 equivalents of the latter are used,
preferably from 1.0 and 1.2 equivalents.
[0058] The present invention likewise features the use of the
disubstituted derivatives of phenylboronic acid of formula (I) and
the compounds (1), (2) and (3) as synthesis intermediates for
preparing vitamin D derivatives.
[0059] Preferably, the compounds (I), (1), (2) and (3) according to
the invention are used as intermediates in the synthesis of
non-steroidal vitamin D derivatives displaying vitamin D
activity.
[0060] More preferably, the non-steroidal vitamin D derivatives are
compounds of formula (IV): ##STR22## in which:
[0061] R1 is a hydrogen atom or an alkyl radical having from 1 to 4
carbon atoms,
[0062] R2 and R3, which may be identical or different, are each an
alkyl radical having from 1 to 4 carbon atoms, and
[0063] R'.sub.1 is an alkyl radical having from 1 to 4 carbon
atoms.
[0064] In the preferred embodiment according to the invention, the
compounds according to the invention are therefore employed in the
synthesis according to the scheme indicated in FIG. 4.
[0065] According to the invention, the compounds of formula (IV)
are preferably prepared from the compound (12) obtained according
to the reaction scheme of FIG. 4. Compound (12) may be obtained
from phenylboronic acid derivative compounds of general formula (I)
according to the invention. A first reaction is a Suzuki coupling
reaction from the derivatives of general formula (I) according to
the invention and an aryl bromide of general formula (II). The
Suzuki reaction product, of general formula (10), is fused with the
benzyl bromide (11) in the presence of a base such as, for example,
potassium carbonate, to give the compounds of general formula (12).
Subsequently, a reaction is employed in accordance with methods
which are well known to one skilled in the art--for example, and
without limitation, such as described in WO 03/050067, which allow
the compound (IV) to be obtained from the compound (12).
[0066] The present invention therefore features the process for
preparing compounds of formula (IV) from phenylboronic acids of the
present invention according to the following steps:
[0067] a) A Suzuki coupling reaction from the compounds of general
formula ##STR23## in which:
[0068] R1 is a hydrogen atom or an alkyl radical having from 1 to 4
carbon atoms,
[0069] R2 and R3, which may be identical or different, are each an
alkyl radical having from 1 to 4 carbon atoms, and
[0070] R4 is the --B(OH).sub.2 radical or the radical of formula:
##STR24## and an aryl bromide of general formula (II): ##STR25## in
which:
[0071] R'.sub.1 is an alkyl radical having from 1 to 4 carbon
atoms, to give the compound of general formula (10): ##STR26## in
which:
[0072] R1 is a hydrogen atom or an alkyl radical having from 1 to 4
carbon atoms,
[0073] R2 and R3, which may be identical or different, are each an
alkyl radical having from 1 to 4 carbon atoms, and
[0074] R'.sub.1 is an alkyl radical having from 1 to 4 carbon
atoms;
[0075] b) the Suzuki reaction product, of general formula (10), is
fused with the benzyl bromide (11) in the presence of a base, such
as potassium carbonate: ##STR27##
[0076] c) liberation of the alcohol functions of the compound (11)
to give the compound (IV).
[0077] The present invention likewise features the compounds of
formula (10), intermediates in the process defined above, of the
following formula: ##STR28## in which:
[0078] R1 is a hydrogen atom or an alkyl radical having from 1 to 4
carbon atoms,
[0079] R2 and R3, which may be identical or different, are each an
alkyl radical having from 1 to 4 carbon atoms, and
[0080] R'.sub.1 is an alkyl radical having from 1 to 4 carbon
atoms; and their use in the synthesis of vitamin D analogues as
described above and in FIG. 2.
[0081] In order to further illustrate the present invention and the
advantages thereof, the following specific examples are given, it
being understood that same are intended only as illustrative and in
nowise limitative. In said examples to follow, all parts and
percentages are given by weight, unless otherwise indicated.
EXAMPLES
Example 1
Step 1: Preparation of Methyl 4-bromo-3-bromomethylbenzoate
[0082] ##STR29##
[0083] In a 6-liter reactor equipped with a condenser, a central
mechanical stirrer and a thermometer, introduce 575 g (2.5 mol) of
methyl 4-bromo-3-methylbenzoate, 3 liters of methylene chloride,
494 g (2.75 mol) of N-bromosuccinimide and 17 g of benzoyl peroxide
(0.05 mol; 70% in water). Heat the mixture at reflux under
irradiation with a 1000 watt lamp for 10 h. Wash the mixture twice
with 1 liter of water, then with 1 liter of saturated sodium
chloride solution. Evaporate the methylene chloride. Recrystallize
the crude product obtained from heptane. This gives 596 g of methyl
4-bromo-3-bromomethylbenzoate in the form of off-white crystals
(Yield=77%)
[0084] Melting point: 100-101.degree. C.
[0085] .sup.1H NMR (CDCl.sub.3; 400 MHz): 3.94 (s; 3H); 4.64 (s:
2H); 7.68 (d; 1H; Jo=8.3 Hz); 7.83 (d.times.d; 1H; Jo=8.3 Hz and
Jm=2.0 Hz); 8.14 (d; 1H; Jm=2.0 Hz)
Step 2: Preparation of Methyl 4-bromo-3-propylbenzoate
[0086] ##STR30##
[0087] In a 6-liter reactor equipped with a condenser, a central
mechanical stirrer, a thermometer and a dropping funnel, introduce
under nitrogen 141 g (0.46 mol) of methyl
4-bromo-3-bromomethylbenzoate, 4 liters of tetrahydrofuran and 8.9
g (0.045 mol) of copper (I) iodide. Cool the mixture to -40.degree.
C. using a bath of acetonitrile and dry ice. Add 168 cm.sup.3 of a
3M solution of ethylmagnesium bromide in diethyl ether and then
allow the reaction temperature to increase to 0.degree. C. After
two hours of reaction hydrolyze the reaction mixture with 1 liter
of 2.5M ammonium chloride solution. Separate the phases and extract
the aqueous phase with 0.7 liter of methylene chloride. Combine the
organic phases and evaporate the solvents. Pour heptane onto the
product obtained and filter off the insoluble product which has
formed. Evaporate the heptane and purify the resulting product by
chromatography on silica gel (heptane/ethyl acetate=95/5). This
gives 51 g of methyl 4-bromo-3-propylbenzoate in the form of
colorless oil. (Yield=43%)
[0088] .sup.1H NMR (CDCl.sub.3; 400 MHz): 1.01 (t; 3H; J.sub.1=7.3
Hz); 1.68 (broad unresolved peak; 2H); 2.76 (t; 2H; J.sub.2=7.6
Hz); 3.92 (s; 3H); 7.61 (d; 1H; Jo=8.3 Hz); 7.71 (d.times.d; 1H;
Jo=8.3 Hz and Jm=1.8 Hz); 7.89 (d; 1H; Jm=1.8 Hz)
Step 3: Preparation of 3-(4-Bromo-3-propylphenyl)pentan-3-ol
[0089] ##STR31##
[0090] In a 1-liter three-necked round-bottomed flask, equipped
with a magnetic stirrer, a thermometer and a dropping funnel,
introduce under nitrogen 47 g (0.18 mol) of methyl
4-bromo-3-propylbenzoate in solution in 250 ml of tetrahydrofuran.
Cool the mixture to -5.degree. C. with the aid of a bath of ice and
sodium chloride. Add 134 cm.sup.3 of a 3M solution of
ethylmagnesium bromide in diethyl ether, then allow the reaction
temperature to increase without exceeding 5.degree. C. After three
hours of reaction, hydrolyze the reaction mixture with 170 cm.sup.3
of 2.5M ammonium chloride solution. Extend the organic phase with
200 cm.sup.3 of ethyl acetate. Separate the phases and extract the
aqueous phase with 2.times.200 cm.sup.3 of methylene chloride.
Combine the organic phases, dry them over sodium sulfate and
evaporate the solvents. This gives 49.8 g of
3-(4-bromo-3-propylphenyl)pentan-3-ol in the form of colorless oil.
(Yield=96%)
[0091] .sup.1H NMR (CDCl.sub.3; 400 MHz): 0.77 (t; 6H; J.sub.2=7.4
Hz); 1.00 (t; 3H; J.sub.1=7.3 Hz); 1.68 (broad unresolved peak;
2H); 1.83 (broad unresolved peak; 4H); 2.73 (t; 2H; J.sub.2=7.7
Hz); 7.05 (d.times.d; 1H; Jo=8.3 Hz and Jm=2.2 Hz); 7.24 (d; 1H;
Jm=2.2 Hz); 7.48 (d; 1H; Jo=8.3 Hz)
Step 4: Synthesis of
4-(1-Ethyl-1-hydroxypropyl)-2-propylphenylboronic acid
[0092] ##STR32##
[0093] In a three-necked flask, introduce under nitrogen 5 g of
3-(4-bromo -3-propylphenyl)pentan-3-ol (17.5 mmol) and 50 cm.sup.3
of tetrahydrofuran. Cool the mixture to -70.degree. C. and add
dropwise 17.5 cm.sup.3 (43.7 mmol) of a 2.5M solution of
n-butyllithium in hexane, over 30 minutes. Leave the reaction
mixture for approximately 2 h with stirring at -70.degree. C. and
then add dropwise 10 cm.sup.3 of triisopropylborate (43.7 mmol),
over 20 minutes. Leave the reaction mixture with stirring for 4 h,
allowing the temperature to increase to 40.degree. C. Hydrolyse the
mixture with saturated NH.sub.4Cl solution and extract twice with
ethyl acetate. Wash the combined organic phases with saturated
sodium chloride solution and evaporate the solvents under vacuum.
This gives 5.4 g of a colorless oil, which is chromatographed on
silica gel (heptane/ethyl acetate=3/1). This gives 1.92 g of
4-(1-ethyl-1-hydroxypropyl)-2-propylphenylboronic acid in the form
of a highly viscous oil. (Yield=44%)
Example 2
Step 1: Preparation of 3-(4-Bromo-3-methylphenyl)pentan-3-ol
[0094] ##STR33##
[0095] In a 4-liter SVL reactor equipped with a magnetic stirrer, a
thermometer and a dropping funnel, introduce under nitrogen 198.7 g
(0.867 mol) of methyl 4-bromo-3-methylbenzoate in solution in 1
liter of tetrahydrofuran. Cool the mixture to -5.degree. C. with
the aid of a bath of ice and sodium chloride. Add 636 cm.sup.3 of a
3M solution of ethylmagnesium bromide in diethyl ether, then allow
the reaction temperature to increase to ambient temperature. After
four hours of reaction, hydrolyze the reaction mixture with 2
liters of a 1 N hydrochloric acid solution. After decanting and
separation, extract the aqueous phase with 0.5 liter of ethyl
acetate. Wash the combined organic phases with 0.4 liter of water
(3.times.). After drying over sodium sulfate, the product obtained
after evaporation of the solvents is purified by chromatography on
silica gel (heptane/ethyl acetate=95/5). This gives 150.2 g of
3-(4-bromo-3-methylphenyl)pentan-3-ol in the form of a colorless
oil (Yield=67%)
[0096] .sup.1H NMR (CDCl.sub.3; 400 MHz): 0.79 (t; 6H; J.sub.2=7.4
Hz); 1.63 (s; 1H); 1.83 (broad unresolved peak; 4H); 2.42 (s; 3H);
7.05 (d.times.d; 1H; Jo=8.3 Hz and Jm=2.2 Hz); 7.27 (d; 1H; Jm=2.2
Hz); 7.48 (d; 1H; Jo=8.3 Hz)
Step 2: Synthesis of
4-(1-Ethyl-1-hydroxypropyl)-2-methylphenylboronic acid
[0097] ##STR34##
[0098] In a three-necked flask, introduce under nitrogen 5 g of
3-(4-bromo -3-methylphenyl)pentan-3-ol (19.4 mmol) and 50 cm.sup.3
of tetrahydrofuran. Cool the mixture to -70.degree. C. and add
dropwise 23.3 cm.sup.3 (58 mmol) of a 2.5M solution of
n-butyllithium in hexane, over 30 minutes. Leave the mixture for
approximately 2 h with stirring at -70.degree. C. and then add
dropwise 13.5 cm.sup.3 of triisopropyl borate (58 mmol), over 20
minutes. Leave the mixture with stirring for 3 h, allowing the
temperature to increase to -10.degree. C. Hydrolyse the mixture
with saturated NH.sub.4Cl solution and extract two times with ethyl
acetate. Wash the combined organic phases with saturated sodium
chloride solution and dry them over sodium sulfate. Evaporate the
solvents under vacuum. This gives 5 g of a colorless oil, which is
chromatographed on silica gel (heptane/ethyl acetate=9/1) to give
4-(1-ethyl-1-hydroxypropyl)-2-methylphenylboronic acid in the form
of a highly viscous oil. (Yield=71%)
[0099] .sup.1H NMR (CDCl.sub.3; 400 MHz): 0.78 (t; 3H; J.sub.2=7.4
Hz); 1.86 (broad unresolved peak; 4H); 2.86 (s; 3H); 7.31 (m; 3H);
8.22 (d; 1H; Jo=8.3 Hz)
Example 3
Synthesis of
3-[3-Propyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]pentan-
-3-ol
[0100] ##STR35##
[0101] In a three-necked flask, introduce under nitrogen 2 g of
3-(4-bromo -3-propylphenyl)pentan-3-ol (7 mmol) and 20 cm.sup.3 of
N,N-dimethylformamide. Add 2.06 g (21 mmol) of potassium acetate
and 1.87 g (7.3 mmol) of bis(pinacol)diborane. Add 0.229 g (0.28
mmol) of
dichloro[1.1'-ferrocenylbis(diphenylphosphane)]palladium(II)
dichloromethane [Pd(dppf)Cl.sub.2] and heat the reaction mixture at
reflux for 2 h 30 min. Hydrolyse the mixture and extract it twice
with ethyl acetate. Wash the combined organic phases with saturated
sodium chloride solution and evaporate the solvents under vacuum.
This gives 3.6 g, which is chromatographed on silica gel
(heptane/ethyl acetate=8/2). This gives 1.55 g of
3-[3-propyl-4-(4,4,5,5-tetramethyl[1,3,2]d
ioxaborolan-2-yl)phenyl]pentan-3-ol in the form of a highly viscous
oil. (Yield=76%) .sup.1H NMR (CDCl.sub.3; 400 MHz): 0.76 (t; 6H;
J.sub.2=7.4 Hz); 0.95 (t; 3H; J.sub.1=7.3 Hz); 1.36 (s; 12H); 1.60
(broad unresolved peak; 2H); 1.67 (s; 1H); 1.84 (broad unresolved
peak; 4H); 2.88 (t; 2H; J.sub.2=7.6 Hz); 7.18 (m; 2H); 7.75 (d; 1H;
Jo=8.4 Hz)
[0102] Each patent, patent application, publication, text and
literature article/report cited or indicated herein is hereby
expressly incorporated by reference.
[0103] While the invention has been described in terms of various
specific and preferred embodiments, the skilled artisan will
appreciate that various modifications, substitutions, omissions,
and changes may be made without departing from the spirit thereof.
Accordingly, it is intended that the scope of the present invention
be limited solely by the scope of the following claims, including
equivalents thereof.
* * * * *